T-cell-mediated immunological barriers to xenotransplantation

Xenotransplantion remains the most viable option for significant expansion of the donor organ pool in clinical transplantation. With the advent of nuclear transfer technologies, the production of transgenic swine has become a possibility. These animals have allowed transplant investigators to overcome humoral mechanisms of hyperacute xenograft rejection in experimental pig-to-non-human primate models. However, other immunologic barriers preclude long-term acceptance of xenografts. This review article focuses on a major feature of xenogeneic rejection: xenogeneic T cell responses. Evidence obtained from both small and large animal models, particularly those using either islet cells or kidneys, have demonstrated that T cell responses play a major role in xenogeneic rejection, and that immunosuppression alone is likely incapable of completely suppressing these responses. Additionally, both the direct and indirect pathway of antigen presentation appear to be involved in these anti donor processes. Enhanced understanding of (i) CD47 and its role in transduced xeno-bone marrow (ii) CD39 and its role in coagulation dysregulation and (iii) thymic transplantation have provided us with encouraging results. Presently, experiments evaluating the possibility of xenogeneic tolerance are underway.     

Using mobile technology to overcome language barriers in medicine

Australia has a large migrant population with variable fluency in English. Interpreting services help ensure that healthcare services are delivered appropriately to these populations. However, the use of professional interpreters in hospitals is expensive. There are also issues with service availability and convenience. Mobile devices containing software with translating abilities have promising potential to improve communication between patients and hospital staff as an adjunct to professional interpreters. It is highly convenient and inexpensive. There are concerns about the accuracy of the interpretation done with such software and more research needs to be carried out to support or allay these concerns. For now, clinically important and medicolegal related interpretation should be undertaken by professional interpreters whereas less crucial tasks may be performed with the help of interpreting software on mobile devices.     

Cervical laminoplasty: Review of complications and strategies to avoid them

This chapter focuses on the laminoplasty technique and the associated indications and contraindications that can help the clinician select the appropriate patient to allow for a successful outcome. Complications encountered in laminoplasty are discussed with a review of surgical and postsurgical management techniques to reduce the incidence and rate.     

Transplantation across previously incompatible immunological barriers

This article reviews recent advances, which allow the transplantation across or around previously incompatible immunological barriers such as a positive crossmatch or ABO blood group incompatibility.     

Interlocking nailing without imaging: the challenges of locating distal slots and how to overcome them in SIGN intramedullary nailing

Placement of the distal interlocking screw is the most difficult part in all intramedullary nail interlocking screw systems and the Surgical Implant Generation Network (SIGN) interlocking system is not an exception. SIGN nails are interlocking implants designed with a precision instrumentation set for use in treatment of long bone fractures without an image intensifier. Locating the distal slots of SIGN nails could be challenging for young SIGN surgeons when treating very complex comminuted fractures and in obese patients. This study was stimulated by a patient who presented one year after surgery with knee pain due to a migrating nail because of missed distal screws. A total of 48 patients divided into two groups of 24 were studied retrospectively and prospectively. The retrospective studies revealed that failure to locate distal locking slots in ten antegrade nailing procedures was due to wrong entry point and comminution of the fracture. The challenges encountered led us to innovating methods to overcome the difficulties of placement of distal screws in a prospective study. Application of methods A and B made location of the distal slots easier in the prospective study even though there were more complex comminuted fractures. The methods also reduced the antegrade operation time by 1 hour 11 minutes. We concluded that SIGN nailing could be challenging and frustrating at the early learning stage. Application of the two innovative methods will make distal slot location easier. They will also make SIGN interlocking nailing less difficult for young SIGN surgeons as they journey through the learning curves.     

Implementing an intravenous insulin protocol in your practice: practical advice to overcome clinical, administrative, and financial barriers

Diabetes mellitus is the fourth most common comorbid condition among hospitalized patients, and 30% of patients undergoing open-heart surgery have diabetes. The link between hyperglycemia and poor outcome has been well described, and large clinical trials have shown that aggressive control of blood glucose with an insulin infusion can improve these outcomes. The barriers to implementing an insulin infusion protocol are numerous, despite the fact that doing so is paramount to clinical success. Barriers include safety concerns, such as fear of hypoglycemia, insufficient nursing staff to patient ratios, lack of administrative and physician support, various system and procedural issues, and resistance to change. Key steps to overcome the barriers include building support with multidisciplinary champions, involving key staff, educating staff, and administrators of the clinical and economic benefits of improving glycemic control, setting realistic goals, selecting a validated insulin infusion protocol, and internally marketing the success of the protocol.     

Blood products: when to use them and how to avoid them

Canadian Journal of Anesthesia/Journal canadien d'anesthésie - Despite the complications associated with transfusions,HBP remains an essential therapeutic modality, without which many...     

Xenotransplantation: the challenge to current psychosocial attitudes

Because of the limited availability of transplantable human organs, xenotransplantation, the use of animal organs as an alternative source, has received considerable attention in recent years. Xenotransplantation would provide an unlimited supply of organs, and these organs would be available whenever required. Although the pig is considered the best source for organs, significant immunologic barriers currently prohibit the implementation of a clinical trial of organ transplantation. However, as medical research gains more insight into the mechanisms underlying rejection of pig organs in primates, therapeutic xenotransplantation is becoming more feasible. Clinical trials of porcine cell transplants are currently underway. Although xenotransplantation will minimize the waiting period for an organ and obviate the feelings of guilt or indebtedness commonly experienced by recipients of human organs, several psychosocial issues may hinder the reintegration of patients into society. For example, concerns that infectious pathogens could be transferred to recipients of pig organs will necessitate life-long monitoring and perhaps even temporary isolation of patients. The possible risk of the spread of a xenozoonosis from the patient to other members of the community may inspire public controversy and even fear, which may have an adverse impact on the patient's emotional state. Additionally, some patients may be psychologically disturbed by the need to incorporate pig organs into their body. This article addresses these and other psychosocial issues that may be associated with clinical xenotransplantation.     

Cellular immunological barriers in xenotransplantation: current status and prospects for avoidance of graft destruction

Genetic modification of pigs (e.g. transgenic expression of human complement regulatory molecules or inactivation of α1,3galactosyltransferase) enabled the development of promising strategies to overcome hyperacute rejection after pig‐to‐primate xenotransplantation. However, cellular rejection still remains a hurdle for successful xenograft survival. Cellular rejection of porcine cells in xenotransplantation models is mediated by macrophages, T cells and NK cells. Activation of human monocytes by pig cells is partly due to the incapacity of porcine ligands to bind the inhibitory receptor SIRPα (signal regulatory protein α). Thus, one approach to impair the ability of human macrophages to phagocyte porcine cells is the overexpression of the human ligand for SIRPα in porcine cells. To inhibit human NK cell reactivity after xenotranslantation transgenic expression of HLA‐E in pigs has been shown to be a promising concept. Cells from these pigs were partially protected from lysis by human NK cells. Our group focuses on manipulation of human anti‐pig T cell responses by negative costimulatory signals. Thus, we asked whether overexpression of PD‐L1 on porcine cells can (i) downregulate human anti‐pig cellular responses in vitro, and (ii) inhibit rat anti‐pig cellular immune responses in vivo. Pig cells overexpressing PD‐L1 triggered reduced proliferation and low amounts of IL‐2, IFNγ, TNF‐alpha, IL‐4, and IL‐5 in human CD4⁺ T cells compared to control pig cells. The concentration of IL‐10, however, was increased. In long‐term cultures of human CD4⁺ T cells and PD‐L1 transfectants a high frequency of CD4⁺ CD25^high FoxP3⁺ cells showed up which had the capacity to suppress the activation of conventional CD4⁺ T cells. Cytotoxic CD8⁺ T cells and NK cells lysed pig control cells very efficiently. In contrast, PD‐L1 transfected pig cells were partially protected from lysis by human effector cells. Overexpression of PD‐L1 on porcine cells was not sufficient to prevent rejection after transplantation under the rat kidney capsule. However, in rats that had been grafted with PD‐L1 expressing cells we observed reduced cellular infiltrates in the kidneys and lower antibody responses compared to rats grafted with control cells. Together these observations support the assumption that PD‐1/PD‐Ligand pathways are interesting targets to prevent cellular immune responses after xenotransplantation. PD‐L overexpression might not only impede the initiation of an anti‐pig T cell response by suppressing CD4⁺ T cells but may also protect pig cells from destruction by cytotoxic effectors. Supported by the Deutsche Forschungsgemeinschaft (Transregio Forschergruppe “Xenotransplantation”, FOR 535).     

Day case surgery: to overcome prejudice

Aim-Background

Ambulatory surgery has become the standard method of care for elective operations in many countries. Nevertheless, day surgery in Greece is far from being established as the modality of choice when performing specific operations. The aim of this study was to evaluate the safety and feasibility of day case surgery in selected operations, as well as patient satisfaction.

Methods

Patients were selected last year over a period of twelve months to undergo operations in the setting of ambulatory surgery. Selection criteria were related to social and medical factors; among others, these included the presence of an accompanying adult, elective surgery, and age under 75 years. We performed 142 operations including laparoscopic cholecystectomies, hernia repair and treatment of perianal diseases. Anaesthetic methods comprised general anaesthesia, local anaesthesia and Transversus Abdominis Plane (TAP) block.

Results

No major complications were recorded for any of the selected surgeries, nor any readmissions. The average cost for the total amount of surgeries was reduced by 40%. This cost reduction was mainly due to the limited use of abdominal drains, restricted preoperative examinations and strict anaesthetic protocol. All patients declared satisfaction with the treatment modality that was offered to them.

Conclusions

Following careful and methodic patient selection, day case surgery can reduce the cost of hospitalization and provide patient satisfaction, in addition to being both achievable and safe.     

Xenotransplantation: Infectious Risk Revisited

Xenotransplantation is a possible solution for the shortage of tissues for human transplantation. Multiple hurdles exist to clinical xenotransplantation, including immunologic barriers, metabolic differences between pigs--the source species most commonly considered--and humans, and ethical concerns. Since clinical trials were first proposed almost 10 years ago, the degree of risk for infection transmitted from the xenograft donor to the recipient has been extensively investigated. A number of potential viral pathogens have been identified including porcine endogenous retrovirus (PERV), porcine cytomegalovirus (PCMV), and porcine lymphotropic herpesvirus (PLHV). Sensitive diagnostic assays have been developed for each virus. Human-tropic PERV are exogenous recombinants between PERV-A and PERV-C sequences and are present in only a subset of swine. Porcine cytomegalovirus can be excluded from herds of source animals by early weaning of piglets. In contrast, the risks associated with PLHV remain undefined. Microbiologic studies and assays for potential xenogeneic pathogens have furthered understanding of risks associated with xenotransplantation. Thus far, clinical xenotransplantation of pig tissues has not resulted in transmission of viral infection to humans; significant risks for disease transmission from swine to humans have not been confirmed. If immunologic hurdles can be overcome, it is reasonable to initiate carefully monitored clinical trials.